Summary: Facial clefts are one of the most common birth defects, affecting 2 out of every thousand babies. While the main causes of facial clefts are unknown, it is obvious that genetics plays a strong role. We've shown that families with one member affected by clefts are 40 times as likely to have a baby with a cleft. Environmental factors are also presumed to play a role in clefts. For example, clefts are easily produced in experimental animals exposed to teratogens. It is likely that humans vary in their genetic susceptibility to teratogens that cause clefts. More than two decades ago, we anticipated that genetic susceptibility would become an important area of epidemiologic research at NIEHS. Accordingly, we selected facial clefts as a condition with both genetic and environmental causes, and we began in 1992 to develop a study to address the causes of clefts. In 1996 we launched a population-based case-control study of facial clefts in Norway. (Norway has one of the highest rates of cleft lip and palate in the world.) The field phase was completed in 2002. We enrolled 88% of all babies with facial clefts born in Norway between 1996 and 2002 (574 cases), and 76% of eligible control infants (763) selected randomly from the population. Mothers of these infants provided detailed information on occupational and other exposures during pregnancy, as well as on nutrition, personal habits and medical history. Biological samples for DNA analysis were collected from cases and controls as well as their mothers, fathers and siblings. These total nearly 4000 people. DNA has been extracted from these samples and assayed for GWAS. We have also had DNA from our newborn cases and controls assayed for methylation changes. We are participating in a multi-study consortium of GWAS in facial clefts, and have contributed to a series of papers identifying gene variants associated with increased risk of facial clefts. The most recent finds an association of a missense variant of the GRHL3 gene with cleft palate (5). We also are taking part in a large consortium of clefts studies to look at associations between common exposures and the risk of facial clefts. We have been able to show a persuasive association between passive smoke exposure and facial clefts (3) -- the first time that passive smoking has been associated with a birth defect. In an extension of our methylation project, we found that maternal age at the time of her pregnancy was associated with epigenetic changes in her offspring. Not only were we able to confirm this association among newborns in an independent data set, we were able to show that the epigenetic changes were persistent into adulthood (6).